U.S. patent number 5,674,507 [Application Number 08/428,865] was granted by the patent office on 1997-10-07 for low crystallinity cellulose excipients.
This patent grant is currently assigned to Biocontrol, Inc.. Invention is credited to Gilbert S. Banker, Shi Feng Wei.
United States Patent |
5,674,507 |
Banker , et al. |
October 7, 1997 |
Low crystallinity cellulose excipients
Abstract
A rapid method to prepare low crystallinity cellulose
(crystallinity 15-45% of polymerization 35-150), suitable for use
as a direct compression excipient (e.g., binder, disintegrant, and
diluent) in pharmaceutical solid dosage forms design and as a
bodying and/or film forming agent in the development of sustained-
and/or film forming agent in the development of sustained- and/or
controlled-release pharmaceutical (topical and transdermal
products), cosmetics, agricultural, personal care and like
products, is provided by reacting cellulose materials with 85% or
higher weight percentage phosphoric acid under controlled sequenced
temperature conditions that involve treatment first at room
temperature for an hour and then at 50.degree.-55.degree. C. for
3-6 hours, followed by separating by a precipitation method,. and
subsequently isolating as a powder or converting into a head or
hydrated form.
Inventors: |
Banker; Gilbert S. (Iowa City,
IA), Wei; Shi Feng (Bloomfield, NJ) |
Assignee: |
Biocontrol, Inc. (Iowa City,
IA)
|
Family
ID: |
25536343 |
Appl.
No.: |
08/428,865 |
Filed: |
April 25, 1995 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
990621 |
Dec 14, 1992 |
5417984 |
|
|
|
Current U.S.
Class: |
424/401; 424/464;
424/488; 424/499; 514/951; 514/960; 536/56; 8/127.1 |
Current CPC
Class: |
A61K
8/731 (20130101); A61K 9/0014 (20130101); A61K
9/06 (20130101); A61K 9/2054 (20130101); A61K
47/38 (20130101); A61Q 19/00 (20130101); C08B
15/02 (20130101); Y10S 514/951 (20130101); Y10S
514/96 (20130101) |
Current International
Class: |
A61K
9/20 (20060101); C08B 15/02 (20060101); C08B
15/00 (20060101); A61K 007/00 (); A61K
009/14 () |
Field of
Search: |
;424/401,195.1,488,499,464 ;8/127.1 ;536/56 ;514/951,960 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Gardner; Sallie M.
Attorney, Agent or Firm: Zarley, McKee, Thomte, Voorhees,
& Sease
Parent Case Text
This is a divisional of application Ser. No. 07/990,621 filed on
Dec. 14, 1992, now U.S. Pat. No. 5,417,984.
Claims
What is claimed is:
1. A low crystallinity powdered cellulosic material having a degree
of polymerization within the range of 35 to 180 and a degree of
crystallinity within the range of 15% to 45% derived from
dehydrating a low crystallinity cellulosic cake material prepared
by reacting cellulosic material with 85%-99% concentrated
phosphoric acid in a sequential temperature reaction with a first
sequential step being at a temperature within the range of
15.degree. C. to 30.degree. C. for up to one hour and a second
sequential step being within the range of 45.degree. C. to
75.degree. C. for from about 2.0 hours to about 10.5 hours, with
the weight ratio of cellulose to phosphoric acid being from 1:2 to
1:20 and then separating the low crystallinity cellulosic material
to provide a cake which is reactivated with an anhydrous organic
solvent followed by drying and grinding to provide a low
crystallinity powdered cellulosic material having a particle size
of less than 1.00 .mu.m.
2. A low crystallinity beaded cellulosic material having a degree
of polymerization within the range of 35 to 180 and a degree of
crystallinity within the range of 15% to 45% prepared from reacting
a cellulosic material with 85%-99% concentrated phosphoric acid in
a sequential temperature reaction with a first sequential step
being at a temperature within the range of 15.degree. C. to
30.degree. C. for up to one hour and a second sequential step being
within the range of 45.degree. C. to 75.degree. C. for from about
2.0 hours to about 10.5 hours, with the weight ratio of cellulose
to phosphoric acid being from 1:2 to 1:20 to provide a low
crystallinity cellulosic product wherein the particles have a size
of less than 1.00 .mu.m which is then separated, water dispersed,
and then spray dried.
3. The product of claim 2 which is prepared using a colloidal
dispersion that contains from about 1% to about 8% concentration of
low crystallinity cellulosic material.
4. The product of claim 2 which is prepared using a colloidal
dispersion that contains from about 3% to about 6% by weight
concentration of colloidally dispersed low crystallinity cellulosic
material.
5. The product of claim 2 which has a primary particle size for the
majority of said particles of from 0.2 .mu.m to about 0.5
.mu.m.
6. The product of claim 5 wherein the particles are spherical.
7. A formulary product selected from the group consisting of
pharmaceutic products, cosmetic products, veterinary products,
agricultural products and personal care products comprising:
a product active and as an excipient-effective amount of low
crystallinity cellulosic material having a degree of polymerization
within the range of 35 to 180 and a degree of crystallinity within
the range of 15% to 45% obtained by reacting said cellulosic
material within the range of 15.degree. C. to 30.degree. C. for up
to one hour and a second sequential step being within the range of
45.degree. C. to 75.degree. C. for from about 2.0 hours to about
10.5 hours with 85% to 99% concentrated phosphoric acid in a
sequential temperature reaction to provide particles of a size less
than 1.00 .mu.m.
8. The product of claim 7 wherein the formulary product is a
pharmaceutic product.
9. The product of claim 7 when the formulary product is a cosmetic
product.
10. The product of claim 7 wherein the formulary product is a
personal care product.
Description
BACKGROUND OF THE INVENTION
Cellulose is the most abundant natural polymer. All forms of plant
life contain cellulose. Because of its nearly ubiquitous
distribution in nature, and human kinds' long exposure to
cellulose, cellulose and its derivatives are generally recognized
as the safest and most acceptable polymer class for use in food and
pharmaceutical products. In its naturally occurring form, cellulose
exists as a fibrous structure composed of arrays of long chains of
cellulose molecules held together by van der Waal forces and
interchain hydrogen bonds. The chemical structure of cellulose
consists of repeating units of .beta.-D glucopyranose rings linked
together by .beta.-1,4-glycosidic linkages. Depending on the
degrees of order of arrangement and hydrogen bonding between
cellulose chains, the crystallinity of the cellulose may range from
50% to 90%. The crystallinity of native cellulose is about 70% (P.
H. Hermans and A. Weidinger, J. Poly. Sci., IV, 135,(1949)). The
amorphous regions in the structure can result from damage during
processing of pulp, from different chain bonding order (i.e.,
occurrence of .beta.-1, 6-linkage instead of the regular
.beta.-1,4-glycosidic bond) or as a result of natural
imperfections. The degree of polymerization of cellulose may range
from 1,000 to 10,000, depending on its source.
The reactions of cellulose with mineral acids to prepare
non-fibrous, low molecular weight (i.e., low degree of
polymerization) cellulose products suitable for use in food,
cosmetics, pharmaceutical, and like products, have been extensively
studied. The reactivity of cellulose towards acids depends on the
crystallinity of the cellulose source, acid concentration, and the
reaction temperature and duration. Several products with varying
degrees of crystallinity and polymerization have been prepared.
Battista (U.S. Pat. Nos. 2,978,446 and 3,146,170) disclose the
preparation of level-off cellulose products suitable for the
manufacture of microcrystalline cellulose--the most commonly and
widely used direct compression excipient for pharmaceutical solid
dosage form design, by reacting a cellulose material with 2.5N
hydrochloric acid at boiling temperature for 15 minutes. According
to the invention, the products produced are highly crystalline in
nature. The level-off degree of polymerization values of products
prepared from native fibers range between 200 and 300, whereas
those prepared from regenerated cellulose lie in the range of from
15 to 60, and products prepared from alkali swollen natural forms
of cellulose are in a degree of polymerization range between 60 and
125. Similar manufacturing procedures, to that described above, are
described in German Patent DAS 1,123,460, using viscose cellulose
as the starting cellulose source, and in Austrian Patent No.
288,805. The use of gaseous HCl, at temperatures below 40.degree.
C., without solvent, to prepare the cellulose precursor for
microcrystalline cellulose, is disclosed in (East) German patent DD
71,282.
Ellefsen et al., in Norsk Skog Industri, 1959, p. 411, describe the
preparation of crystalline cellulose products by dissolving the
starting cellulose source in 38-40.3% concentrated hydrochloric
acid at 20.degree. C., followed by precipitating with water. In
U.S. Pat. No. 4,357,467, a similar procedure to the foregoing,
using 37-42% HCl acid at 30.degree.-50.degree. C., is employed to
prepare cellulose products having substantially reduced
crystallinity (17-83%), and a low degree of polymerization
(10-200). Compared to native and regenerated cellulose, the low
crystallinity cellulose products show improved dispersibility in
water, increased compatibility with basic compounds such as
starches, proteins, and lipids, and are useful as excipients in the
preparation of tablets and confectionery products.
Greidinger et al (U.S. Pat. No. 3,397,198) disclose the preparation
of an amorphous degraded cellulose by treating a cellulose material
with 65-75% sulfuric acid at a temperature of 35.degree.-45.degree.
C. for a period of no longer than 10 minutes. The amorphous product
is suitable for use in cleaners, cosmetic preparations, foodstuffs
or as a filler for materials such as plaster-of-paris or
adsorbents.
V. M. Brylyakove (SU Patent 4266981) describe the preparation of
microcrystalline cellulose utilizing 3-5% nitric acid, sulfuric
acid or hydrochloric acid and a fatty acid (C.sub.10-20) at
96.degree.-98.degree. C. The fatty acid enhances the efficiency of
the process.
Other references that can be cited, pertinent to the preparation of
microcrystalline cellulose, are: CA 111 (8) 59855w; CA 111 (8)
59787a; CA 108 (18) 152420y; CA 104 (22) 188512m; CA 104 (24)
209374K; CA 104 (24) 193881C; CA 99 (24) 196859y; CA 98 (12)
95486y; CA 94 (9) 64084d; and CA 85 (8) 48557u.
The interaction of cellulose with phosphoric acid has been the
subject of several publications. S. M. Hudson and J. A. Cuculo,
Macromol. Sci. -Rev. Macromol. Chem., C18, 6-7 (1980) and J. O.
Warwicker, in Cellulose and Cellulose Derivatives," N. M. Bikales
and L. Segal, eds., Wiley, New York, N.Y. (1971), Vol. V, Part IV,
p. 325-79, describe that the swelling and/or dissolution of
cellulose in phosphoric acid depend(s) on the concentration of the
acid. In concentration range between 71-80%, the swelling of
cellulose is rapid. Further increases in the concentration causes
dissolution of the cellulose. According to Hudson and Cuculo, the
dissolution of cellulose is incomplete when the acid solution
contains higher than 85% and less than 92% phosphoric acid. S. N.
Danilov and N. F. Gintse, Zh. Obsch. Khim., 26, 3014 (1956),
describe that the cellulose dissolves more readily with increasing
temperature, with a maximum dissolution rate at
40.degree.-50.degree. C.
Bellamy and Holub (U.S. Pat. No. 4,058,411) disclose the use of
80-85% phosphoric acid for the decrystallization of cellulose.
According to the invention, the starting cellulose source, having
particles about one millimeter in length and diameter, is reacted
with phosphoric acid at room temperature, with or without the
presence of a surfactant, for a prolonged period until a gel is
formed. The product is then precipitated from the gel using an
aqueous solution of tetrahydrofuran. The amorphous product can be
used as a source of glucose or as a substrate for microbial
production of antibiotics and other metabolites, single cell
proteins and industrial alcohol.
In Swiss Patent No. 79,809, a method is described for the
depolymerization of cellulose using a mixture of hydrochloric acid
and sulfuric acid or phosphoric acid (25-35%) at temperatures below
50.degree. C., is provided. There is, however, no mention of the
crystallinity of the product in the disclosure.
We have found that the treatment of cellulose with phosphoric acid,
under controlled sequenced temperature conditions, provides a rapid
method of preparing low crystallinity cellulose products that are
suitable for use as excipients in cosmetic, food, pharmaceutical,
and like products.
Accordingly, the primary objective of this invention is to provide
a rapid method for converting fibrous cellulose material to useful
low crystallinity cellulose excipients using phosphoric acid.
A further objective of the present invention is to provide new low
crystallinity cellulose excipients suitable for use in cosmetic,
pharmaceutical, personal care, and like products.
Still another objective of this invention is to provide a bodying
agent and/or film forming agent composed of hydrated low
crystallinity cellulose.
These and other objectives of the present invention will be more
apparent from the discussion that follows.
SUMMARY OF THE INVENTION
The present invention provides new low crystallinity cellulose
(LCC) excipients, namely, low crystallinity powder cellulose
(LCPC), low crystallinity bead cellulose (LCBC), and low
crystallinity hydrated cellulose (LCHC), suitable for use in
cosmetic, pharmaceutical, personal care, and like products,
prepared by reacting a cellulose material with 80% or higher weight
percentage phosphoric acid, (preferably 85% to 99%) first at room
temperature (i.e. from 15.degree. C. to 30.degree. C.) for up to
about an hour, and then at 50.degree.-60.degree. C. for a period of
time (typically 3-6 hours), sufficient to dissolve the cellulose in
the acid. As used herein, the term low crystallinity cellulose is
intended to refer to a white solid material that precipitates when
water or an appropriate organic solvent is combined with the above
reaction solution, which can then be readily isolated as a powder
(LCPC), or converted into a bead form (LCBC) or into an aqueous
colloidal dispersion (LCHC). The degree of crystallinity of the
products, prepared under the conditions of this invention, ranges
between about 15% and 45%, and the degree of polymerization values
range from about 35 to 150.
Therefore, the present invention also provides a rapid method
whereby cellulosic materials, such as cotton linters, purified
cotton papers, .alpha.-cellulose, purified wood pulp,
microcrystalline cellulose, or like materials, can be readily
converted into a low crystallinity cellulose product.
Owing to the greatly reduced degree of crystallinity and submicron
particle size (0.2-0.5 .mu.m), the LCC products show high enthalpy
of immersion (LCPC:-31.01 cal/g; LCBC:-19.66 cal/g) and large
surface area (LCPC: 2.45 m.sup.2 /g; LCBC: 2.33 m.sup.2 /g).
Avicel.RTM.PH-101 (FMC Corporation), the most commonly and widely
used microcrystalline cellulose product, has a surface area of only
1.40 m.sup.2 /g and shows an enthalpy of immersion value of only
-16.74 cal/g. LCPC shows strong bonding/binding properties on
compression, and plastic deformations with a lower mean yield
pressure upon compression (82 MPa versus. 125 MPa for
Avicel.RTM.PH-101), which explains its superiority as a binder in
tablets. The LCBC serves as an excellent disintegrate in tablets
because of its capillary structure, that allows for rapid
penetration for water, for water interactions. Other factors
contributing to its superior disintegrating properties include a
lack of entanglement or interlocking between bead particles, the
release of stored elastic mechanical energy as the compressed but
intact beads expand as the tablets disintegrate, the strong
affinity of bead particles for interactions with water, and the
release of high heat of immersion.
LCHC can be used as a novel film forming system, and/or as a
bodying agent or as a carrier or co-carrier for a wide range of
bioactive compounds or cosmetic compounds in systems for
application to skin or hair, thereby producing substantive,
controlled and/or sustained-release topical and transdermal
formulations that have superior cosmetic and elegance features.
Such formulations may be devoid of fats, waxes, oils, or
surfactants, thereby producing natural, hypoallergenic and
non-irritating topical systems. The present LCHC material can also
carry bioactive materials to plant surfaces, again producing
substantive, biocompatible, controlled and/or sustained release
systems, which have the added advantage of being ultimately
biodegradable in the environment.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a scanning electron micrograph of low-crystallinity
powdered cellulose (LCPC) of this invention.
FIG. 2 is a scanning electron micrograph of low-crystallinity bead
cellulose (LCBC) of this invention.
FIG. 3 is a graph showing yield of the low-crystalline cellulose
(LCC) product yield in comparison with reaction time at 50.degree.
C.
FIG. 4 is a graph showing degree of polymerization of LCC with an
increase in reaction time at 50.degree. C.
FIG. 5 is an x-ray powder diffraction pattern of LCC and for
comparison purposes of a prior art hydroxycellulose product.
FIG. 6 is a plot showing the crystallinity of LCC increased with an
increase in reaction time at 50.degree. C.
FIG. 7 is a plot showing the inverse relationship between degree of
polymerization and LCC crystallinity.
FIGS. 8 and 9 show the effects of swelling time at room temperature
on the degree of polymerization of LCC products.
FIG. 10 compares the heat of immersion of LCC product and a
conventional product.
FIG. 11 shows the moisture sorption isotherm of low crystalline
powdered cellulose (LCPC) against water vapor pressure.
FIG. 12 shows the thickness of tablets prepared at different
compression pressures for tablets using LCBC of this invention and
other materials showing LCBC tablets show the least reduction.
FIG. 13 shows a scanning electron micrograph of the LCBC tablet
with 13(a) showing the surface and 13(b) a cross section of the
tablet.
FIGS. 14, 15A and 15B show comparisons scanning electron
micrographs of LCPC and Avicel.RTM.PH-101 tablets for comparison
with FIG. 13.
FIG. 16 compares crushing strengths of LCPC, LCBC,
Avicel.RTM.PH-101 and lactose tablets, indicating superior binding
properties of LCPC.
FIG. 17 shows Heckel plot analysis of LCPC compared to
Avicel.RTM.PH-101, again demonstrating superior binding properties
of LCPC.
FIGS. 18 and 19 show the effect of crystallinity and degree of
polymerization on the crushing strengths.
FIG. 20 shows that as the degree of polymerization increases the
crystallinity of LCPC first decreases and then increases.
FIG. 21 shows the effect of the degree of crystallinity on the
water penetration rate.
DETAILED DESCRIPTION OF THE INVENTION
According to the invention, the new low crystallinity cellulose
product, readily convertible into powder, bead and hydrated forms,
is prepared by reacting a cellulose material with 80% or higher,
preferably 85% or higher, weight percentage phosphoric acid, first
at room temperature (i.e. 15.degree. C. to 20.degree. C.) for about
an hour, and then at a temperature of 45.degree.-75.degree. C.,
preferably 50.degree.-60.degree. C., for about 2 to 10.5 hours,
preferably about 3-6 hours. It is important that the phosphoric
acid be present in a sufficient quantity to initially uniformly
impregnate the cellulose material, and that the reaction
temperature sequence be observed. Although the minimum
weight-to-volume ration of cellulose to phosphoric acid that can be
used is about 1:2, it is preferred, for the purpose of this
invention, to employ a ratio of 1:2-1:20 most preferably 1:3 to
1:10. The higher ratios (i.e., higher than 1:10) of cotton linters
to phosphoric acid can also be used, but are wasteful of acid and
hence less cost effective. The proper treatment of cellulose with
phosphoric acid at room temperature causes uniform swelling of the
cellulose. As a result, the crystallinity of the cellulose is
largely destroyed. At 50.degree.-60.degree. C., the cellulose
rapidly hydrolyzes, and consequently, dissolves in the acid to give
a viscous solution. The viscosity of the reaction solution
decreases as the hydrolysis of the cellulose progresses.
The decrystallization/depolymerization of cellulose can be
performed at room temperature, but the depolymerization reaction is
very slow and can take several days to produce the desired low
crystallinity cellulose product with the desired degree of reduced
polymerization. If the reaction between cellulose and phosphoric
acid is performed at 50.degree.-60.degree. C., without an initial
one hour treatment at room temperature, the product is a highly
crystalline product.
The low crystallinity cellulose dissolved in the acid can be
suitably separated by combining the reaction mixture under high
shear mixing with water or an organic solvent which is miscible
with phosphoric acid, but which does not dissolve LCC (e.g.,
acetone, methanol, and ethanol). Water solvent mixtures may also be
used. Filtration, followed by washing the white solid with water to
a near neutral pH, provides a hydrated LCC cake. If desired, the
neutralization of the acid, associated with the solid, can also be
suitably effected by washing initially with an aqueous base such as
aqueous alkali metal hydroxide or ammonium hydroxide, followed by
water to remove the residual base from the solid. The filtration of
the LCC solid can be readily performed using any of the
conventional separation techniques, such as vacuum filtration,
decantation, and centrifugation.
The aqueous colloidal dispersion of LCC is prepared by suspending
and homogenizing the hydrated LCC cake in water. A high-shear mixer
or a homogenizer or a household blender can be used. The LCHC
dispersions containing 10% or higher weight percentage LCC contents
are creams to heavy pastes, whereas those with more than 3% and
less than 10% LCC are lotion-like in consistency. The viscosities
of the lotion-type dispersions increase with an increase in the LCC
content. All dispersions containing less than 3% LCC settle during
storage. Such dispersions, however, can be readily stabilized by
adding minor, but effective amounts of a water soluble viscosity
imparting agent such as, carboxymethylcellulose, methyl cellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulose,
polyvinylpyrrolidone, cross-linked acrylic acid polymers
(Carbopol.RTM.Resins), and the like. A water insoluble suspending
agent such as bentonite, fumed silicas, modified clays (Thixogel),
or the like, can also be used. LCHC also forms stable dispersions
in hydroalcoholic mixtures, in water miscible solvents e.g.
ethanol, methanol, isopropanol, acetone or a mixed water
solvent.
Irrespective of the amount of LCC present, these dispersions form
extremely adhesive white films on human skin and hair and on a
variety of other surfaces (e.g., glasses, metals, and woods). If
desired, minor but effective amounts of an appropriate plasticizer
such as glycerin, propylene glycol, mineral oil, citric acid
esters, N,N-m-diethyltoluamide, diethyl phthalate, dibutyl
sebacate, and the like, can be added to the LCC dispersions. When
plasticized, these dispersions form transparent, flexible,
non-tacky, and non-oily films.
The aqueous colloidal dispersions of LCC are microbiologically
stable at room temperature for many months. It is, however,
preferred to add minor but effective amounts of one or more of the
commonly used preservatives such as the phenols, benzoates,
parabens, quats (quaternium-15) and the like, to increase
resistance and inhibition of any microbial growth.
The preparation of LCPC is achieved by dehydrating the LCC cake
with an anhydrous organic solvent, such as acetone, methyl alcohol,
iso-propanol, n-butanol, and the like, followed by drying at room
temperature or at 50.degree.-80.degree. C., preferably at
70.degree.-75.degree. C. During drying, LCPC converts into a loose
agglomerate powder, which can be ground to a desired particle size.
If desired, the LCPC can also be prepared by freeze drying the wet
LCC cake, or by milling spray dried materials.
The LCBC is prepared by spray drying an aqueous colloidal
dispersion of LCC. The suitable concentration range of the LCC
dispersions, for spray drying, is from about 1% to 8%, preferably
about 3-6%. The size of the primary particles of LCBC ranges
between 0.2 .mu.m and about 1.0 .mu.m, but most of the particles
are about 0.5 .mu.m or smaller. The particle size of the LCBC
agglomerate, however, ranges from 5 to 250 .mu.m (FIG. 2), but a
typical product may have about 90% or more of its particles in a
size smaller than 45 .mu.m. Dispersions containing higher than 8%
LCC do not have adequate flow and atomization properties, owing to
their highly viscous nature, and are, therefore, not suitable for
spray drying.
The yield of LCC ranges from 60% to 90%. As shown in FIG. 3, it
decreases with an increase in the reaction time at
50.degree.-60.degree. C. A scanning electron micrograph of LCPC,
prepared by dehydration of an LCC cake with iso-propanol, followed
by drying at 75.degree. C., is shown in FIG. 1, while that of an
LCBC is reproduced in FIG. 2. The LCPC appears as an agglomerated
powder consisting of primary spherical particles of about 0.5 .mu.m
size, whereas the LCBC agglomerates are spherical in shape
comprising several primary particles of 0.2 to 0.5 .mu.m size.
The degree of polymerization of LCC decreases with an increase in
the reaction duration at 50.degree.-60.degree. C., as shown in FIG.
4. It ranges from 35 to 180, preferably 80 to 135. The linear
relationship between the reaction time and the logarithm of the
degree of polymerization values indicates that the depolymerization
of cellulose by phosphoric acid, under the conditions of this
invention, is a first-order reaction, with a rate constant value of
0.314 hour.sup.-1. The first-order rate constant for the
depolymerization of cellulose at room temperature is
4.79.times.10.sup.-3 hour.sup.-1.
The x-ray powder diffraction pattern of LCC is shown in FIG. 5.
Also included in the figure are the powder diffractograms of a
hydrocellulose product (prepared according to the method provided
in U.S. Pat. No. 3,146,170), employed as a 100% crystalline
standard, and of Avicel.RTM.PH-101. Except for an additional line
at 7.4A, the diffraction pattern of LCC is very similar to those
displayed by the Avicel.RTM.PH-101 and the hydrocellulose samples.
Based on the integration of all diffraction peaks (i.e., the total
area under the peaks), the degrees of crystallinity for LCC and
Avicet.RTM.PH-101 are 15% and 81% respectively.
The crystallinity of the LCC increases with an increase in the
reaction time at 50.degree.-60.degree. C., as shown in FIG. 6. By
way of explanation, and not wishing to be limited thereby, as noted
above, the degree of polymerization of the product decreases with
an increase in the reaction time. This causes an increase in the
particle's surface area. The larger the surface area, the greater
the interaction between particles (cellulose chains), and
consequently, the higher the crystallinity. This inverse
relationship between degree of polymerization and crystallinity of
LCC products is shown in FIG. 7. It must be noted that the
crystallinity of microcrystalline cellulose increases with an
increase in the degree of polymerization. Thus, in this invention,
where a simultaneous low degree of polymerization and low degree of
crystallinity are sought, very precise control of reaction times
and temperatures are required.
In FIGS. 8 and 9, the effects of swelling time (i.e., duration of
acid treatment at room temperature) on the degree of polymerization
and crystallinity of LCC products, are compared. The results show
no significant changes in the two properties when the reaction
duration, at room temperature, is increased from one hour to
fourteen hours. These findings, and the fact that the direct
treatment of cellulose with phosphoric at 50.degree.-60.degree. C.,
without an initial treatment at room temperature, produces a highly
crystalline product, suggest that an initial swelling period of
about one hour or less at room temperature, is critical to the
preparation of LCC.
Compared to LCPC, LCBC shows a slightly higher degree of
crystallinity. This, probably, occurs due to the recrystallization
of LCC, to a small extent, in water, during spray drying.
The mean specific surface areas of LCPC and LCBC particles are 2.45
m.sup.2 /g and 2.33 m.sup.2 /g, respectively. The small difference
in specific area between the powder and bead materials confirms
that the primary particles comprising the beads are loosely
associated, and hence lose little of their effective surface area.
LCBC shows a higher bulk density and lower porosity compared to
LCPC. The bulk densities for the LCBC and LCPC are 0.85 g/cm.sup.3
and 0.431 g/cm.sup.3, and the porosity values are 49.1% and 72.7%,
respectively. This difference in the bulk densities and porosities
of the two products are due to the differences in the particle's
shapes. The LCBC particles, as shown in FIG. 2, are highly
spherical in shape, which facilitates a more tightly packed powder
bed, whereas LCPC is a highly agglomerated powder composed of
irregular-shape particles, which, when packed, has more void spaces
as a result of entanglement or interlocking of particles. The
densities and porosities of the LCPC and LCBC compacts, prepared by
compressing 0.5 grams of the LCPC and LCBC each at 3000 lb for 30
seconds, are 1.381 g/cm.sup.3 and 1.241 g/cm.sup.3 and 21.4% and
12.6%, respectively. The density values suggest a larger volume
reduction for the LCPC compact than for the LCBC compact. This
occurs because the LCBC particles retain their integrity, to a
large extent, under compression, whereas the LCPC particles undergo
significant plastic flow, thereby filling void spaces and forming
new bonds on the true contact areas.
Calorimetric methods have been widely used to study the heat of
wetting or other properties of water insoluble excipients such as
interactions between additives. Calorimetry measures a progressing
change of an extensive property, enthalpy, as one physical state is
changing to another state. The enthalpy of immersion,
(.DELTA.H.sub.i), is the heat of immersion of the solid,
representing energy changes due to wetting, hydration, swelling,
surface changes, or the release of stored energy of solids in
water. Thus, cellulose excipients having different levels of
crystallinity would be expected to show different enthalpies of
immersion. FIG. 10 compares the heat of immersion of various LCC
products, provided by this invention, and Avicel.RTM.PH-101 having
a percent of crystallinity of 80%. The negative .DELTA.H.sub.i
values obtained indicate that the interaction between cellulose and
water is an exothermic reaction. The -.DELTA.H.sub.i increases with
a decrease in the crystallinity of the cellulose. This is because
as the crystallinity decreases more hydroxyl groups become
available for interactions with water, and consequently, the
.DELTA.H.sub.i increases. The .DELTA.H.sub.i values for the LCPC
and LCBC products, having 27% crystallinity, are -31.01 cal/g and
-19.66 cal/g, respectively, whereas the corresponding value for the
Avicel.RTM.PH-101 is -16.74 cal/g. When LCBC is compressed at a
pressure of 3000 lb for 30 seconds, the .DELTA.H.sub.i is increased
by 9.8%. This increase in the .DELTA.H.sub.i value on compression
is due to the increased defect structure, and release of elastic
energy stored in the LCBC compact as a result of compression. The
.DELTA.H.sub.i of the LCC is also dependent on the moisture content
present, increasing with a decrease in the moisture amount. For
example, the .DELTA.H.sub.i values for LCPC containing 5% and 0%
moisture are 24.72.+-.0.53% cal/g and 31.02.+-.1.92 cal/g,
respectively.
The heat of wetting, .DELTA.H.sub.w, of LCC, calculated from
.DELTA.H.sub.i using Hess's Law, is -6.9 cal/g, about 27.1% higher
than that reported for Avicel.RTM.PH-101 (R. G. Hollenbeck, G. E.
Peck, and D. O. Kildsig, J. Pharm. Sci., 67, 1599 (1978)). The
moisture sorption isotherm of LCPC against water vapor pressure is
shown in FIG. 11. The moisture content increases with an increase
in the water vapor pressure.
The preparations of LCC, LCPC, LCBC, and LCHC and their
applications in the formulation of a variety of pharmaceutical,
cosmetic, and personal care products are illustrated by the
following examples, which are not to be construed as limiting.
EXAMPLE 1
Decrystallization/depolymerization of Cellulose Using Phosphoric
Acid
One thousand milliliters of 85-86% phosphoric acid was placed in an
appropriate size flat-bottom glass or polyvinylidine fluoride
container. To this was added 100 grams of cotton linter sheet,
broken into small pieces, or cotton linter fluff. The thoroughly
wetted cellulosephosphoric mixture was then allowed to stand at
room temperature for about one hour. The reaction container was
then placed in a water-bath that had been adjusted to
50.degree.-60.degree. C. After about one and one half to two hours
of heating, the reaction mixture was stirred using a mechanical
stirrer equipped with an acid-resistant propeller and a shaft.
Mixing and heating were continued until a light cream colored
solution was formed (about 2-3 hours). The reaction solution was
immediately poured into water with vigorous stirring. The water
volume can be about five-to-ten times that of the acid volume. An
immediate precipitation of white solid occurred. The solid was then
filtered using a buchner funnel and a Whatman Grade-113 filter
paper. An extensive washing of the solid with water followed, to a
near neutral pH of the wash water, to produce a hydrated low
crystallinity cellulose (LCHC), with an 85-90% yield (based on the
dried weight basis). [If desired, the white solid residue can be
washed first with an aqueous solution of a base, such as sodium or
potassium hydroxide or ammonium hydroxide, and then with water to
remove the inorganic phosphates.]
EXAMPLE 2
Preparation of Low Crystallinity Powder Cellulose (LCPC)
The hydrated white cake, prepared according to the procedure of
Example 1, was dispersed in an appropriate volume of methanol,
ethanol, acetone, or iso-propanol. The mixture was stirred with a
mechanical stirrer for about 15 minutes, or until a uniform
dispersion was formed and then filtered. This process was repeated
three-to-five times to ensure complete depletion of water from the
cellulose. The dehydrated low crystallinity cellulose residue was
then broken into small lumps with a spatula, and dried either at
room temperature overnight or at 75.degree. C. for 4-6 hours.
Following drying, the low crystallinity cellulose powder was ground
with a mortar and pestle or using a pulverizing blender, to reduce
the particle size of the agglomerates to below 125 .mu.m.
EXAMPLE 3
Preparation of Low Crystallinity Bead Cellulose (LCBC)
The low crystallinity hydrated cellulose, prepared according to the
procedure of Example 1, was homogenized in an appropriate amount of
distilled purified water, to give an LCC concentration of about
4-8%. The resulting homogeneous colloidal dispersion was then spray
dried, using a Nitro Utility Spray Dryer (Nitro Atomizer, Ltd.,
Columbia, Md., USA), equipped with a 12 cm diameter radial vane
centrifugal atomizer, operating at 24,000 rpm and an inlet
temperature of about 200.+-.5, and an outlet temperature of
100.+-.3. The low crystallinity bead cellulose powder, thus
obtained, was collected, and passed through a #120(125 mm)
sieve.
EXAMPLE 4
Comparative Evaluation of LCPC and LCBC as Direct Compression
Excipients in Tablets
A. As Binders
0.5 grams of LCPC and LCBC, prepared according to the procedures of
Examples 1-3, were separately compressed for 20 seconds, without a
lubricant, into cylindrical flat-face tablets at different
compression loads using the same punch (flat-faced) and die (11 mm
diameter). Tablets of Avicel.RTM.PH-101 and lactose, employed for
comparison purposes, were also prepared in the same manner. The
results obtained are discussed below:
The thickness of the tablets prepared at different compression
pressures is depicted in FIG. 12. LCBC tablets show the least
volume reduction, whereas Avicel.RTM.PH-101 and LCPC tablets
exhibit the highest. The lactose tablets show smaller volume
reduction, compared to the LCPC tablets (and Avicel.RTM.PH-101),
but higher than for the LCBC tablets. The low compressibility of
the LCBC material is attributed to its inability to undergo plastic
flow, under compression. This is reflected in the scanning electron
micrograph (of the LCBC tablet) depicted in FIG. 13, which shows a
deformed compressed bead structure (FIG. 13b), with large void
spaces (FIG. 13a), and definite boundaries between the particles.
In comparison, the scanning electron micrographs of LCPC and
Avicel.RTM.PH-101 tablets (FIGS. 14 and 15) demonstrate strong
interactions between the primary particles, with disappearance of
some boundaries, especially in regions near the edges of the
tablet. This accounts for the higher compressibility of these
materials. The smaller thickness of the lactose tablets, compared
to the LCBC tablets, is due to the fragmentation of the lactose
particles, under compression, which fill the interparticle spaces
to produce a relatively tightly packed compact.
FIG. 16 compares the crushing strengths of LCPC, LCBC,
Avicel.RTM.PH-101, and lactose tablets. The highest crushing
strength values for the LCPC tablets clearly indicate superior
binding properties of the LCPC material. The poorer compatibility
(i.e. binding properties) of the Avicel.RTM.PH-101, compared to
LCPC, is due to its higher crystallinity. This is because as the
crystallinity increases, a smaller number of hydroxyl groups become
available for interactions. As a result, the weaker tablet is
formed. Further support for the superior binding properties of the
LCPC material, compared to Avicel.RTM.PH-101, is provided by Heckel
Plot analysis (FIG. 17). The linear portions of the plots indicate
that both LCPC and Avicel.RTM.PH-101 undergo plastic flow under
compression. The mean yield pressure values, calculated from the
slopes of the linear portions of the curves, are 82 MPa and 125 MPa
for the LCPC and Avicel.RTM.PH-101, respectively. The lower (mean
yield pressure) value for the LCPC indicates that the LCPC material
has a greater ability to deform plastically at lower pressure than
Avicel.RTM.PH-101. Further, LCPC, owing to the agglomeration of
primary particles, probably deforms along many planes, whereas
Avicel undergoes plastic deformation along slip planes only (R. F.
Shangraw, in "Pharmaceutical Dosage Forms: Tablets," H. A.
Lieberman, L. Lachman, and J. B. Schwartz, eds., Marcel Dekker,
Inc., New York, 2nd ed., Vol. 1, p. 195-96, 209-216 (1989)). These
factors make LCPC more compressible than Avicel.RTM.PH-101. The
porosities of the LCPC and Avicel.RTM.PH-101 compacts correspond to
12.5% and 15.4%, respectively, further documenting the tighter
packing of the LCPC than Avicel.RTM.PH-101 under compression.
LCBC tablets are stronger than lactose tablets. This is because
LCBC, owing to its low crystallinity and submicron particle size,
demonstrates more extensive hydrogen bonding. In comparison,
lactose forms bonds only in the glassy region which constitutes a
very small portion of the lactose crystals.
The results of viscoelastic analysis, which provides the energy
change in the unloading phase of the tabletting process, including
the work due to the elastic deformation and viscous deformation,
are presented in Table 1.
TABLE 1 ______________________________________ Cellulose form LCBC
LCPC AVICEL PH-101 ______________________________________ Avg. Wt.
0.538 0.543 0.535 P(MPa) 153 173 109 W.sub.o (J/cm.sup.3) -12.30
-13.04 -5.23 W.sub.i (J/cm.sup.3).sub.3 9.55 9.00 3.75 W.sub.Fdx
(J/cm.sup.3) -2.73 -3.31 -1.45 W.sub.L (J/cm.sup.3) 30.52 38.92
29.62 Increment 7 8 5 ______________________________________
The stress P values decease in the order from LCPC to LCBC and to
AVICEL PH-101. Both LCPC and LCBC show higher negative values for
the work due to elastic deformation than AVICEL PH-101. This is due
to the submicron particle size of the LCPC and LCBC which provides
larger surface area for interactions, and consequently, requires
more work for the elastic deformation. AVICEL PH-101 shows
extensive interlocking of the fibers, and thereby demonstrates a
lower value of the work of elastic deformation. The higher W.sub.i
values for the LCPC and LCBC, compared to AVICEL PH-101, suggest
that the LCC primary particles undergo a greater extent of viscous
flow in the unloading phase of the tabletting process. This results
in an increase in the contact area, which facilitates stronger
interactions to consolidate the tablet while dissipating the excess
energy in the forms of heat and entropy. The higher negative force
displacement work values for the LCPC and LCBC, compared to AVICEL
PH-101, are due the absence of any interlocking of primary
particles in the LCPC and LCBC aggregates. There is no difference
in the loading work among the LCPC, LCBC, and AVICEL PH-101. The
incremental values, which reflect the extent of expansion in the
unloading phase, are consistent with the work values due to elastic
deformation. The viscoelastic analysis further documents the
superiority of LCPC and LCBC materials as to tablet excipients,
compared to microcrystalline cellulose.
The effects of crystallinity and degree of polymerization on the
crushing strengths of the LCPC tablets are depicted in FIGS. 18 and
19. Tablets for this study were prepared by compressing 0.5 grams
of LCPC, having different crystallinity and degree of
polymerization values, at 3000 lb for 20 seconds. As shown in FIG.
18, the crushing strengths of the tablets increased from 20 Kg to
100 Kg when the crystallinity of the LCC decreased from 45% to 12%.
This shows that as the crystallinity decreases, stronger tablets
are formed, as would be expected. FIG. 19 shows that the crushing
strength of the LCPC tablet first increases then decreases with an
increase in the degree of polymerization. This is because as the
degree of polymerization increases the crystallinity of LCPC first
decreases and then increases, as shown in FIG. 20.
The effect of the particle size on the fluidity of the LCPC
compared to a like particle size AVICEL PH-101 powder and on the
crushing strength is compared in Table 2.
TABLE 2 ______________________________________ Cellulose Particle
size Flow rate Crushing Strength form (.mu.m) g/sec Kg
______________________________________ LCPC 50 1.75 .+-. 0.31 74.8
.+-. 2.9 LCPC 125-350 5.61 .+-. 0.91 76.2 .+-. 1.4 AVICEL PH-101 50
1.30 .+-. 0.34 58.4 .+-. 1.8
______________________________________
Generally, the larger the particle size of a powder, the better the
fluidity or powder flow. However, the crushing strength of plastic
materials has been shown to decrease with an increase in particle
size (M. Sheik-Salem and J. T. Fell, Acta Pharm. Suec., 19, 391
(1982); A. H. DeBoer et al., Pharm. Weekblad, Sci. Ed., 8, 145
(1986); N. R. Anderson, G. S. Banker, and G. E. Peck, J. Pharm.
Sci., 71, 7 (1982)). Thus, the loss of crushing strength,
accompanying an increase of particle size, is of general concern in
tablet making although larger particles characteristically provide
much better powder flow. The data listed in Table 2 indicate that
LCPC, irrespective of particle size and flow rate, provide tablets
with nearly the same crushing strength values. The significance of
this unique property of LCPC is that the preparation of LCPC with a
larger particle size, that demonstrates excellent powder flow, at
the same time, produces compacts with the same strong cohesion
properties as the fine particles. Both adequate powder flow and
strong compact cohesion properties are desirable features in
excipients used in tablet production. The reason that LCPC
possesses this unique property, among tablet excipients, is that
the LCPC particles are actually agglomerates, each made up of
hundreds to thousands of individual colloidal particles.
B. As Disintegrants
Tablets of LCPC, LCBC, and AVICEL PH-101, each weighing 0.5 grams,
were prepared using a Carver press at either 1000 lb for 20 seconds
or at 3000 lb for 30 seconds. The heats of immersion, water
penetration rate and the disintegration time of the tablets are
presented in Table 3.
TABLE 3 ______________________________________ Water Heat
Penetration Disintegration of Immersion Sample Rate (mg/sec) Time
.increment..sup.H.sub.i ______________________________________ LCBC
3.347 5.0 seconds -21.59 LCPC 0.0 -- not detd. AVICEL PH-101 1.724
>1 hour -13.63 ______________________________________
The water penetration data show that water penetrates much more
rapidly in the LCBC tablets than in AVICEL PH-101 tablets. The LCPC
tablets did not show any appreciable penetration of water. The
greater water penetration rate of the LCBC tablets is due to its
capillary structure (FIGS. 2 and 12) and reduced degree of
crystallinity. LCPC, though also having a reduced degree of
crystallinity, undergoes high plastic flow under compression,
causing the primary particles to pack themselves very tightly (see
FIG. 14). The penetration of water in the AVICEL tablet occurs
through the void spaces produced as a result of entanglement or
interlocking of primary particles during compression (see FIG.
15):
The effect of the degree of crystallinity on the water penetration
rate is depicted in FIG. 21. As is evident from the Figure, the
water penetration increases with a decrease in the crystallinity,
because more and more free hydroxyl groups become available for
interactions.
The rapid disintegration of the LCBC tablet compared to the AVICEL
PH-101 tablet is due to its greater capillary action. Other factors
that contribute to its superior disintegrating properties include
the lack of entanglement of primary particles, release of stored
mechanical (elastic) energy as the tablet disintegrates, stronger
affinity for interaction with water, and the release of a higher
heat of immersion.
EXAMPLE 5
Comparative Evaluation of LCPC and AVICEL PH-101 as Binders in
Acetaminophen Tablets
Test tablets were prepared by thoroughly mixing 320 mg of
acetaminophen, a poorly compressible material, with 175 mg of LCPC
or AVICEL PH-101, and 5 mg of magnesium stearate, followed by
compression at a pressure of 3000 lb for 20 seconds using a Carver
press. A commercial acetaminophen tablet, Tylenol.RTM., having the
same tablet size and drug content, was also tested for comparison.
The results are presented in Table 4.
TABLE 4 ______________________________________ Tablet
Disintegration Time Crushing Strength Type (min) (Kg)
______________________________________ LCPC 11.4 .+-. 0.2 9.00 .+-.
1.14 AVICEL PH-101 14.6 .+-. 2.1 6.53 .+-. 0.40 Tylenol 0.68 .+-.
0.03 8.70 .+-. 0.03 ______________________________________
The higher crushing strength of the LCPC-acetaminophen tablets
compared to the AVICEL PH-101 tablets is consistent with the
superior cohesion properties of the LCPC. The LCPC-acetaminophen
also disintegrates faster than the AVICEL tablet (11.4 min. vs.
14.6 min.). This is due to the stronger affinity of the LCC
material with water. Compared to LCPC and AVICEL-acetaminophen
tablets, the Tylenol.RTM. tablet disintegrates very rapidly, and
shows an intermediate crushing strength value.
The strong cohesion properties of the LCPC, coupled with its
excellent flow properties and effectiveness as a disintegrant in
drug mixture systems, demonstrate the unique usefulness and
superiority of LCPC as a direct compression combined
binder/disintegrant/diluent excipient material in tablet
making.
EXAMPLE 6
Disintegration of LCBC-Griseofulvin Tablets
LCBC-Griseofulvin tablets, comprised of 215 grams of LCBC and 250
grams of griseofulvin, were prepared in the same manner as
described in Example 6. The disintegration time and the crushing
strength values of the tablets are listed in Table 5. Fulvicin U/F,
a commercial griseofulvin tablet containing the same amount of drug
and of the same size as the test tablet, was employed as a
reference.
TABLE 5 ______________________________________ Tablet
Disintegration Time Crushing Strength Type (min) (Kg)
______________________________________ LCBC 0.88 .+-. 0.15 23.8
.+-. 0.61 Fulvicin U/F 1.48 .+-. 0.18 11.6 .+-. 0.93
______________________________________
The LCBC-griseofulvin tablet demonstrated a faster disintegration
time (0.88 minutes versus 1.48 minutes) and a stronger crushing
strength (23.8 Kg versus 11.6 Kg) than the commercial griseofulvin
tablet.
EXAMPLE 7
Preparation of Cream, Lotion and Spray Formulations Using LCHC
Owing to its high suspendibility in water and hydroalcoholic
solvent systems and its ability to form extremely adhesive films on
the skin. LCHC can be used to prepare a wide range of
pharmaceutical (topical and transdermal), cosmetic, agricultural,
and like products. Conventional formulation procedures can be used
to prepare cream, lotion, and spray products, utilizing the present
LCHC material. For example, various formulation ingredients (i.e.,
viscosity enhancing agents, plasticizers, preservatives, active
drugs, etc.) can be simply mixed with the LCHC dispersion using a
mechanical stirrer, followed by homogenization of the mixture. If
desired, heated oil and water phases can be prepared separately,
combined, and the resultant blend allowed to cool to room
temperature with constant agitation. Formulations, prepared
utilizing the present LCHC material, rub-in smoothly on the skin,
and rapidly dry to form Uniform, transparent, invisible, flexible,
and non-tacky and non-oily films.
Active ingredients can be selected from a wide variety of
cosmetics, pharmaceuticals, insecticides, herbicides, rodenticides,
fungicides, pigments, insect repellents or fragrances.
The following examples are provided to more fully illustrate the
utility of the LCHC material in topical formulations, and should
not be construed as limiting the scope thereof.
A. Antihistamine/Skin Protectant Lotion
The procedure of Example 1 was repeated to produce an LCHC cake
that contained 15% LCC. 24.1 grams of this cake was taken in 15
grams of water, and then thoroughly mixed with 5.0 grams of
diphenhydramine hydrochloride, and 0.5 grams of glycerin. The
mixture was then homogenized to produce a white stable lotion
product. This product rubs-in smoothly on the skin, and can be used
for relief from itching due to minor skin irritations.
B. Anti-acne Lotion and Cream
An LCHC cake containing 12.4% of LCC was prepared according to the
procedure of Example 1. To 28.3 grams of this cake, equivalent to
about 3.5 grams of the LCC, was added about 43.7 grams of water.
The mixture was stirred until a homogeneous suspension was formed.
While continuing stirring, 0.3 grams of the cross-linked
polyacrylic acid (Carbomer 934P, Goodrich), 0.15 grams of methyl
paraben, and 0.10 grams of propyl paraben, were added to the LCHC
mixture. Once the Carbomer was completely dissolved, 14.3 grams of
30% benzoyl peroxide U.S.P. was added. The mixture was then
homogenized to produce a homogeneous dispersion. At this stage,
while continuing stirring, 13.0 grams of glycerin was added to the
mixture. After stirring the mixture for about an hour, 0.3. grams
of triethanolamine was added. An immediate increase in the
viscosity occurred. The lotion product, thus obtained, was stirred
for an additional one to one and a half hour, and then homogenized.
The product is cosmetically superior and elegant. Being 100% water
based, the product, when applied on the skin, rapidly dries to form
uniform, transparent, virtually invisible and non-oily films. The
oil-based systems tend to aggravate acne conditions.
A cream product, exhibiting similar cosmetic elegancy and
characteristics as were observed with the lotion product, was
prepared using the same procedure as described above. The
compositions of the various ingredients were: LCHC 32.0 grams
(corresponded to 5.0% LCC), Carbomer 934P 0.5 grams,
triethanolamine 0.5 grams, methyl paraben 0.15 grams, propyl
paraben 0.10 grams, benzoyl peroxide 14.3 grams, glycerin 14.0
grams, and water to 100 grams.
C. Anti-inflammatory Cream
48.1 grams of the LCHC cake (equivalent to about 7.5 grams of the
LCC), 0.5 grams of the Carbomer 934P, 0.15 grams of methyl paraben,
and 0.10 grams of propyl paraben were combined with 39.6 grams of
water. The mixture was stirred to produce a homogeneous dispersion.
10.0 grams of glycerin and 1.0 grams of hydrocortisone were then
added to the mixture with stirring. Further stirring for an
additional hour, followed by homogenization produced a 1%
hydrocortisone cream product.
D. External Analgesic Cream
A mixture containing 22.4 grams of LCHC cake (equivalent to 3.5
grams of the LCC), 1.0 grams of Tween 20, 0.25 grams of Carbomer
934P, 0.15 grams of methyl paraben, 0.10 grams of propyl paraben,
and 25.6 grams water, was stirred until a homogeneous dispersion
was formed. To this, while continuing stirring, a solution that
comprised 10.0 grams of menthol and 30.0 grams of methyl
salicylate, was added. To the resulting mixture were then added
10.0 grams of glycerin, 0.25 grams of triethanolamine, and 0.25
grams of hydroxypropylmethylcellulose (Methocel.RTM.Krm, Dow
Chemicals), in the order written. The resulting cream product was
stirred for an additional hour and then homogenized. It was stored
in a half or one ounce aluminum tube that had a lining of a
phenolic epoxy polymer. The product is physically and chemically
stable, and rubs-in smoothly on the skin to produce a monolithic
non-greasy film having prolonged release characteristics.
E. Spray System for Perfumes
A cosmetically elegant spray formulation was prepared by
homogenizing a dispersion that comprised 22.4 grams of LCHC cake
(equivalent to 3.0 grams of LCC), 0.15 grams of methyl paraben,
0.10 grams of propyl paraben, 0.5 grams of Tween 20, 0.1 grams of
Carbomer 934P, 0.1 grams of triethanolamine, 10.0 grams of
glycerin, and 1.0 to 3.0 grams or more of a perfume. The product
can be sprayed utilizing a standard pump spray package
assembly.
* * * * *